Taxane Particles and Their Use

ABSTRACT

Compositions are provided that include having at least 95% by weight of a taxane, or a pharmaceutically acceptable salt thereof, where the particles have a mean bulk density between about 0.050 g/cm 3  and about 0.15 g/cm 3 , and/or a specific surface area (SSA) of at least 18 m 2 /g, 20 m 2 /g, 25 m 2 /g, 30 m 2 /g, 32 m 2 /g, 34 m 2 /g, or 35 m 2 /g. Methods for making and using such compositions are also provided.

CROSS REFERENCE

This application is a continuation of U.S. application Ser. No.16/669,310 filed Oct. 30, 2019, which is a continuation of U.S.application Ser. No. 15/895,197 filed Feb. 13, 2018, now U.S. patentSer. No. 10/507,195 issued Dec. 17, 2019, which is a continuation ofU.S. application Ser. No. 15/499,397 filed Apr. 27, 2017, now U.S. Pat.No. 9,918,957 issued which Mar. 20, 2018, which is a continuation ofU.S. application Ser. No. 15/261,108 filed Sep. 9, 2016, which is adivisional of U.S. patent application Ser. No. 15/174,505 filed Jun. 6,2016, now U.S. Pat. No. 9,814,685 issued Nov. 14, 2017, which claimspriority to U.S. Provisional Patent Application Ser. No. 62/171,060filed Jun. 4, 2015, 62/171,001 filed Jun. 4, 2015, and 62/171,008 filedJun. 4, 2015, each incorporated by reference herein in its entirety.

BACKGROUND

Dissolution rate is a key parameter in determining the rate and extentof drug absorption and bioavailability. Poor aqueous solubility and poorin vivo dissolution are limiting factors for in vivo bioavailability ofmany drugs. Thus, in vitro dissolution rates are recognized as animportant element in drug development, and methods and compositions forincreasing the dissolution rates of poorly soluble drugs are needed.

SUMMARY OF THE INVENTION

In a first aspect, the invention provides compositions, comprisingparticles including at least 95% by weight of a taxane, or apharmaceutically acceptable salt thereof, wherein the particles have oneor both of the following characteristics:

(i) a mean bulk density between about 0.050 g/cm³ and about 0.15 g/cm³,and/or;

(ii) have a specific surface area (SSA) of at least 18 m²/g, 20 m²/g, 25m²/g, 30 m²/g, 32 m²/g, 34 m²/g, or 35 m²/g.

In one embodiment, the taxane is selected from the group consisting ofpaclitaxel, docetaxel, cabazitaxel, taxadiene, baccatin III, taxchininA, brevifoliol, and taxuspine D, or a pharmaceutically acceptable saltthereof. In another embodiment, the taxane is selected from the groupconsisting of paclitaxel, docetaxel, and cabazitaxel, or apharmaceutically acceptable salt thereof.

In a further embodiment, the taxane is paclitaxel or a pharmaceuticallyacceptable salt thereof, and wherein the particles have a mean bulkdensity between about 0.050 g/cm³ and about 0.12 g/cm³, or between about0.060 g/cm³ and about 0.11 g/cm³. The paclitaxel particles may have aspecific surface area (SSA) of at least 18 m²/g, 20 m²/g, 25 m²/g, 30m²/g, 32 m²/g, 34 m²/g, or 35 m²/g. The paclitaxel particles may have aSSA of between about 22 m²/g and about 40 m²/g, 25 m²/g and about 40m²/g, 30 m²/g and about 40 m²/g, or between about 35 m²/g and about 40m²/g. The paclitaxel particles may have a bulk density of between about0.060 g/cm³ and about 0.11 g/cm³ and a SSA of between about 22 m²/g andabout 40 m²/g. In another embodiment, at least 40% (w/w) of thepaclitaxel is dissolved in 30 minutes or less in a solution of 50%methanol/50% water ((v/v)) at 37° C. and pH 7.0 in a USP II paddleapparatus operating at 75 RPM.

In one embodiment, the taxane is docetaxel or a pharmaceuticallyacceptable salt thereof, and wherein the particles have a mean bulkdensity between about 0.050 g/cm³ and about 0.12 g/cm³, or between about0.06 g/cm³ and about 0.1 g/cm³. The docetaxel particles may have a SSAof at least 18 m²/g, 20 m²/g, 25 m²/g, 30 m²/g, 35 m²/g, 40 m²/g, or 42m²/g. The docetaxel particles may have a SSA of between about 40 m²/gand about 50 m²/g, or between about 43 m²/g and about 46 m²/g. Thedocetaxel particles may have a bulk density of between about 0.06 g/cm³and about 0.1 g/cm³ and a SSA of between about 40 m²/g and about 50m²/g. In a further embodiment, at least 20% (w/w) of the docetaxel isdissolved in 30 minutes or less in a solution of 15% methanol/85% water(v/v) at 37° C. and pH 7.0 in a USP II paddle apparatus operating at 75RPM.

In a further aspect, the invention provides compositions comprisingparticles including at least 95% by weight of paclitaxel, or apharmaceutically acceptable salt thereof, wherein the particles have aspecific surface area (SSA) of at least 12 m²/g. The paclitaxelparticles may have a SSA of at least 12 m²/g, 15 m²/g, 20 m²/g, 25 m²/g,30 m²/g, 32 m²/g, 34 m²/g, or 35 m²/g. In one embodiment, at least 40%(w/w) of the paclitaxel is dissolved in 30 minutes or less in a solutionof 50% methanol/50% water (v/v) at 37° C. and pH 7.0 in a USP II paddleapparatus operating at 75 RPM.

In another aspect, the invention provides compositions comprisingparticles including at least 95% by weight of paclitaxel, wherein atleast 40% (w/w) of the paclitaxel is dissolved in 30 minutes or less ina solution of 50% methanol/50% water (v/v) in a USP II paddle apparatusoperating at 75 RPM. The invention also provides compositions comprisingincluding at least 95% by weight of docetaxel, wherein at least 20%(w/w) of the docetaxel is dissolved in 30 minutes or less in a solutionof 15% methanol/85% water (v/v) at 37° C. and pH 7.0 in a USP II paddleapparatus operating at 75 RPM.

The compositions of the invention may comprise particles have a meanparticle size of between about 0.4 μm and about 1.2 μm, or between about0.6 μm and about 1.0 μm. The particles may be uncoated and excludepolymer, protein, polyethoxylated castor oil and polyethylene glycolglycerides composed of mono-, di- and triglycerides and mono- anddiesters of polyethylene glycol. The compositions may further beincorporated into a suspension, which further comprises apharmaceutically acceptable aqueous carrier. The composition may furthercomprise one or more components selected from the group consisting ofpolysorbate, methylcellulose, polyvinylpyrrolidone, mannitol, andhydroxypropyl methylcellulose. The compositions may comprise by weightat least 96%, 97%, 98%, 99%, or 100% of the compound.

The invention further provides methods for treating a tumor, comprisingadministering to a subject with a tumor an amount effective to treat thetumor of a composition according to any embodiment or combination ofembodiments of the invention. In one embodiment, the tumor may beselected from the group consisting of a breast tumor, an ovarian tumor,a lung tumor, a bladder tumor, a prostate tumor, a bone tumor, a stomachtumor and a pancreatic tumor. In another embodiment, the composition isadministered intraperitoneally, such as by perfusion or as a bolus intothe peritoneal cavity. In one embodiment, the intraperitonealadministration is initiated after removal of ascites fluid from theperitoneal cavity. In another embodiment, the subject is a humansubject.

The invention further provides methods for making compound particles,comprising:

(a) introducing (i) a solution comprising at least one solvent and atleast one solute comprising a compound of interest into a nozzle inlet,and (ii) a compressed fluid into an inlet of a vessel defining apressurizable chamber;

(b) passing the solution out of a nozzle orifice and into thepressurizable chamber to produce an output stream of atomized droplets,wherein the nozzle orifice is located between 2 mm and 20 mm from asonic energy source located within the output stream, wherein the sonicenergy source produces sonic energy with an amplitude between 10% and100% during the passing, and wherein the nozzle orifice has a diameterof between 20 μm and 125 μm; and

(c) contacting the atomized droplets with the compressed fluid, to causedepletion of the solvent from the atomized droplets, to produce compoundparticles, wherein steps (a), (b), and (c) are carried out undersupercritical temperature and pressure for the compressed fluid.

In one embodiment, the method further comprises:

(d) contacting the atomized droplets produced in step (c) with ananti-solvent to cause further depletion of the solvent from the compoundparticles, wherein step (d) is carried out under supercriticaltemperature and pressure for the anti-solvent.

In one embodiment, a flow rate of the solution through the nozzle has arange from about 0.5 mL/min to about 30 mL/min. In a further embodiment,the sonic energy source comprises one of a sonic horn, a sonic probe, ora sonic plate. In another embodiment, the sonic energy source has afrequency between about 18 kHx and about 22 kHz, or about 20 kHz.

The methods may further comprise:

(e) receiving the plurality of particles through the outlet of thepressurizable chamber; and

(f) collecting the plurality of particles in a collection device.

In one embodiment, the compound is a taxane. The method of any one ofclaims 30-35 wherein the compound is a taxane. Exemplary taxanes mayinclude paclitaxel, docetaxel, cabazitaxel, taxadiene, baccatin III,taxchinin A, brevifoliol, and taxuspine D, or a pharmaceuticallyacceptable salt thereof. In a specific embodiment, the taxane isselected from the group consisting of paclitaxel, docetaxel, andcabazitaxel, or a pharmaceutically acceptable salt thereof. In oneembodiment, the solvent is selected from the group consisting ofacetone, ethanol, methanol, dichloromethane, ethyl acetate, chloroform,acetonitrile, and suitable combinations thereof. In various embodiments,the compressed fluid and/or the anti-solvent may be super criticalcarbon dioxide. In one embodiment, the compound is paclitaxel and thesolvent comprises acetone. In another embodiment, the compound isdocetaxel and the solvent comprises ethanol. In a further embodiment,the method is carried out between 31.1° C. to about 60° C., and atbetween about 1071 psi and about 1800 psi.

The invention also provides compound particles prepared by the method ofany embodiment or combination of embodiments of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an electron micrograph of exemplary paclitaxel particles ofthe invention.

FIG. 2 is an electron micrograph of raw paclitaxel particles.

FIG. 3 illustrates a cross-section view of an example nozzle assembly,according to an example embodiment.

FIG. 4 illustrates a cross-section view of another example nozzleassembly, according to an example embodiment.

FIG. 5 illustrates a perspective view of a particle collection device,according to an example embodiment.

FIG. 6 illustrates a top view of the particle collection device,according to an example embodiment.

FIG. 7 illustrates a cross-section view of the particle collectiondevice, according to an example embodiment.

FIG. 8 illustrates another cross-section view of the particle collectiondevice, according to an example embodiment.

FIG. 9 illustrates another cross-section view of the particle collectiondevice, according to an example embodiment.

FIG. 10 illustrates a perspective view of a support frame, according toan example embodiment.

DETAILED DESCRIPTION OF THE INVENTION

All references cited are herein incorporated by reference in theirentirety. As used herein, the singular forms “a”, “an” and “the” includeplural referents unless the context clearly dictates otherwise. “And” asused herein is interchangeably used with “or” unless expressly statedotherwise. All embodiments of any aspect of the invention can be used incombination, unless the context clearly dictates otherwise.

As used herein, “about” means +/−5% of the recited value.

In one aspect, the present invention provides compositions, comprisingparticles including at least 95% by weight of a taxane, or apharmaceutically acceptable salt thereof, wherein the particles have oneor both of the following characteristics:

(i) a mean bulk density between about 0.050 g/cm³ and about 0.15 g/cm³,and/or

(ii) have a specific surface area (SSA) of at least 18 m²/g, 20 m²/g, 25m²/g, 30 m²/g, 32 m²/g, 34 m²/g, or 35 m²/g.

The inventors have unexpectedly been able to produce compositionscomprising the recited taxane particles that have a mean bulk densitybetween about 0.050 g/cm³ and about 0.15 g/cm³, and/or a specificsurface area (SSA) of at least 18 m²/g an SSA using novel methods forproducing the particles as described herein. As shown in the examplesthat follow, the increased specific surface area and decreased bulkdensity of the taxane particles result in significant increases indissolution rate compared to the raw taxane and to milled taxaneproducts used for comparison. Dissolution takes place only at asolid/liquid interface. Therefore, increased specific surface area willincrease the dissolution rate due to a larger number of molecules on thesurface of the particle having contact with the dissolution media. Thebulk density takes into account the macrostructure and inter-particlespace of a powder. Parameters that contribute to the bulk densityinclude particle size distribution, particle shape, and the affinity ofthe particles for each other (i.e., agglomeration). Lower powder bulkdensities yield faster dissolution rates. This is due to the ability ofthe dissolution media to more readily penetrate the interstitial orinter-particle spaces and have greater contact with the surface of theparticles. Therefore, each of the increased specific surface area andthe decreased bulk density result in the significant increase indissolution rate for the taxane particles of the invention compared tothe unprocessed or raw material, and the milled taxane product used forcomparison. This provides a significant improvement for use of thetaxane particles of the invention in, for example, tumor treatment.

As used herein, the “specific surface area” is the total surface area ofthe paclitaxel particle per unit of paclitaxel mass as measured by theBrunauer-Emmett-Teller (“BET”) isotherm (i.e.: the BET SSA). As will beunderstood by those of skill in the art, the “taxane particles” includeboth agglomerated taxane particles and non-agglomerated taxaneparticles; since the SSA is determined on a per gram basis it takes intoaccount both agglomerated and non-agglomerated taxane particles in thecomposition. The BET specific surface area test procedure is acompendial method included in both the United States Pharmaceopeia andthe European Pharmaceopeia.

As used herein, the bulk density of the taxane particles is the mass ofthe totality of particles in the composition divided by the total volumethey occupy when poured into a graduated cylinder. The total volumeincludes particle volume, inter-particle void volume, and internal porevolume.

Taxanes are a class of diterpenoids containing a taxadiene core that arevery poorly soluble in water. The taxane particles of the invention maybe any suitable taxane, including but not limited to paclitaxel,docetaxel, cabazitaxel, taxadiene, baccatin III, taxchinin A,brevifoliol, and taxuspine D, combinations thereof, or pharmaceuticallyacceptable salts thereof. In one embodiment, the taxane is selected fromthe group consisting of paclitaxel, docetaxel, and cabazitaxel, or apharmaceutically acceptable salt thereof.

The “taxane particles” refers to particles of taxane that do not includean added excipient. Taxane particles are different than “particlescontaining taxane”, which are particles that contain taxane and at leastone added excipient. Taxane particles of the invention exclude apolymeric, wax or protein excipient and are not embedded, contained,enclosed or encapsulated within a solid excipient. Taxane particles ofthe invention may, however, contain impurities and byproducts typicallyfound during preparation of taxane. Even so, taxane particles compriseat least 95%, at least 96%, at least 97%, at least 98%, at least 99% or100% taxane, meaning the taxane particles consist of or consistessentially of substantially pure taxane. In one embodiment, the taxaneparticles are uncoated and exclude polymer, protein, polyethoxylatedcastor oil and polyethylene glycol glycerides composed of mono-, di- andtriglycerides and mono- and diesters of polyethylene glycol.

The compositions of the invention have a mean particle size of betweenin the range of about 0.2 μm to about 5 μm, about 0.4 μm to about 3 μmor about 0.5 μm to about 1.4 μm. In a further embodiment, thecompositions have a mean particle size of between about 0.4 μm and about1.2 μm. In another embodiment the mean particle size is between about0.4 μm and about 1.2 μm, or between about 0.6 μm and about 1.0 μm.

In one embodiment, the taxane is paclitaxel or a pharmaceuticallyacceptable salt thereof, and the particles have a mean bulk densitybetween about 0.050 g/cm³ and about 0.12 g/cm³. In another embodiment,the paclitaxel particles have a mean bulk density between about 0.060g/cm³ and about 0.11 g/cm³.

In a further embodiment, the taxane is paclitaxel or a pharmaceuticallyacceptable salt thereof, and wherein the paclitaxel particles have aspecific surface area (SSA) of at least 18 m²/g. In various furtherembodiments, the paclitaxel particles have a SSA of at least 20 m²/g, 25m²/g, 30 m²/g, 32 m²/g, 34 m²/g, or 35 m²/g. In a further embodiment,the paclitaxel particles have a SSA of between about 22 m²/g and about40 m²/g, between about 25 m²/g and about 40 m²/g, between about 30 m²/gand about 40 m²/g, or between about 35 m²/g and about 40 m²/g.

In one preferred embodiment, the paclitaxel particles have a mean bulkdensity of between about between about 0.050 g/cm³ and about 0.12 g/cm³and a SSA of at least 30 m²/g. In another preferred embodiment, thepaclitaxel particles have a mean bulk density of between about betweenabout 0.050 g/cm³ and about 0.12 g/cm³ and a SSA of at least 35 m²/g. Inone the paclitaxel particles have a mean bulk density of between aboutbetween about 0.050 g/cm³ and about 0.12 g/cm³ and a SSA of betweenabout 30 m²/g and about 40 m²/g. In another preferred embodiment, thepaclitaxel particles have a mean bulk density of between about 0.060g/cm³ and about 0.11 g/cm³ and a SSA of between about 30 m²/g and about40 m²/g. In another preferred embodiment, the paclitaxel particles havea mean bulk density of between about 0.060 g/cm³ and about 0.11 g/cm³and a SSA of at least 30 m²/g. In a further embodiment, the paclitaxelparticles have a mean bulk density of between about 0.060 g/cm³ andabout 0.11 g/cm³ and a SSA of at least 35 m²/g. These variousembodiments are exemplified in the examples that follow.

In any of these various embodiments, the paclitaxel particles mayinclude at least 4.16×10¹³ gram paclitaxel, or a pharmaceuticallyacceptable salt thereof per paclitaxel particle.

In another embodiment, at least 40% (w/w) of the paclitaxel in thepaclitaxel particles of the composition is dissolved in 30 minutes orless in a solution of 50% methanol/50% water (v/v) in a USP II paddleapparatus operating at 75 RPM. pH 7 was used, and the solubility of thetaxanes are not effected by pH. In another embodiment, the dissolutionstudies are carried out at 37° C.

In another embodiment, the taxane is docetaxel or a pharmaceuticallyacceptable salt thereof, and the docetaxel particles have a mean bulkdensity between about 0.050 g/cm³ and about 0.12 g/cm³. In a furtherembodiment, the mean bulk density of the docetaxel particles is betweenabout 0.06 g/cm³ and about 0.1 g/cm³.

In another embodiment, the taxane is docetaxel or a pharmaceuticallyacceptable salt thereof, and wherein the docetaxel particles have a SSAof at least 18 m²/g. In various further embodiments, the docetaxelparticles have a SSA of at least 20 m²/g, 25 m²/g, 30 m²/g, 35 m²/g, 40m²/g, or 42 m²/g. In a further embodiment, the docetaxel particles havea SSA of between about 40 m²/g and about 50 m²/g. In another embodiment,the docetaxel particles have a SSA of between about 43 m²/g and about 46m²/g.

In one preferred embodiment, the docetaxel particles have a mean bulkdensity between about 0.050 g/cm³ and about 0.12 g/cm³ and a SSA of atleast 30 m²/g. In another preferred embodiment, the docetaxel particleshave a mean bulk density between about 0.050 g/cm³ and about 0.12 g/cm³and a SSA of at least 35 m²/g. In a further preferred embodiment, thedocetaxel particles have a mean bulk density between about 0.050 g/cm³and about 0.12 g/cm³ and a SSA of at least 40 m²/g. In one preferredembodiment, the docetaxel particles have a mean bulk density betweenabout 0.050 g/cm³ and about 0.12 g/cm³ and a SSA of between about 40m²/g and about 50 m²/g. In another preferred embodiment, mean bulkdensity of the docetaxel particles is between about 0.06 g/cm³ and about0.1 g/cm³ and the SSA is between about 40 m²/g and about 50 m²/g. Thesevarious embodiments are exemplified in the examples that follow.

In any of these various embodiments, the docetaxel particles may includeat least 4.16×10⁻¹³ grams docetaxel, or a pharmaceutically acceptablesalt thereof per docetaxel particle.

In another embodiment, at least 20% (w/w) of the docetaxel is dissolvedin 30 minutes or less in a solution of 15% methanol/85% water (v/v) in aUSP II paddle apparatus operating at 75 RPM. A neutral pH was used wherethe solubility of the taxanes are not effected by pH. In anotherembodiment, the dissolution studies are carried out at 37° C.

In a further aspect, the invention provides compositions comprisingparticles including at least 95% by weight of paclitaxel, or apharmaceutically acceptable salt thereof, wherein the particles have aspecific surface area (SSA) of at least 12 m²/g. In various embodiments,the paclitaxel particles have an SSA of at least 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, or 40 m²/g. In various further embodiments, thepaclitaxel particles have an SSA of between about 12 m²/g and about 40m²/g, about 14 m²/g and about 40 m²/g, about 15 m²/g and about 40 m²/g,about 16 m²/g and about 40 m²/g, about 17 m²/g and about 40 m²/g, about18 m²/g and about 40 m²/g, about 19 m²/g and about 40 m²/g, about 20m²/g and about 40 m²/g, about 22 m²/g and about 40 m²/g, about 26 m²/gand about 40 m²/g, about 30 m²/g and about 40 m²/g, between about 20m²/g and about 29 m²/g, between about 20 m²/g and about 28 m²/g, betweenabout 20 m²/g and about 26.2 m²/g, between about 22 m²/g and about 29m²/g, between about 22 m²/g and about 28 m²/g, between about 22 m²/g andabout 26.2 m²/g, between about 32 m²/g and about 39 m²/g, between about32 m²/g and about 38.5 m²/g, between about 32 m²/g and about 35 m²/g,between about 35 m²/g and about 40 m²/g, and between about 35 m²/g andabout 38.5 m²/g. In other embodiments, the paclitaxel particles have anSSA of:

(a) between 16 m²/g and 31 m²/g or between 32 m²/g and 40 m²/g;

(b) between 16 m²/g and 30 m²/g or between 32 m²/g and 40 m²/g;

(c) between 16 m²/g and 29 m²/g or between 32 m²/g and 40 m²/g;

(d) between 17 m²/g and 31 m²/g or between 32 m²/g and 40 m²/g;

(e) between 17 m²/g and 30 m²/g or between 32 m²/g and 40 m²/g;

(f) between 17 m²/g and 29 m²/g, or between 32 m²/g and 40 m²/g;

(g) between 16 m²/g and 31 m²/g or between 33 m²/g and 40 m²/g;

(h) between 16 m²/g and 30 m²/g or between 33 m²/g and 40 m²/g;

(i) between 16 m²/g and 29 m²/g or between 33 m²/g and 40 m²/g;

(j) between 17 m²/g and 31 m²/g or between 33 m²/g and 40 m²/g;

(k) between 17 m²/g and 30 m²/g or between 33 m²/g and 40 m²/g;

(l) between 17 m²/g and 29 m²/g, or between 33 m²/g and 40 m²/g;

(m) between 16 m²/g and 31 m²/g, or 32 m²/g;

(h) between 17 m²/g and 31 m²/g, or 32 m²/g;

(i) between 16 m²/g and 30 m²/g, or 32 m²/g;

(j) between 17 m²/g and 30 m²/g, or 32 m²/g;

(k) between 16 m²/g and 29 m²/g, or 32 m²/g;

(l) between 17 m²/g and 29 m²/g, or 32 m²/g;

(m) between 16 m²/g and 31 m²/g, or 33 m²/g;

(n) between 17 m²/g and 31 m²/g, or 33 m²/g;

(o) between 16 m²/g and 30 m²/g, or 33 m²/g;

(p) between 17 m²/g and 30 m²/g, or 33 m²/g;

(q) between 16 m²/g and 29 m²/g, or 33 m²/g; or

(r) between 17 m²/g and 29 m²/g, or 33 m²/g.

In another embodiment, at least 40% (w/w) of the paclitaxel in thepaclitaxel particles of the composition is dissolved in 30 minutes orless in a solution of 50% methanol/50% water (v/v) in a USP II paddleapparatus operating at 75 RPM. pH 7 was used, and the solubility of thetaxanes are not effected by pH. In another embodiment, the dissolutionstudies are carried out at 37° C.

In another aspect, the present invention provides compositions,comprising particles including at least 95% by weight of paclitaxel,wherein at least 40% (w/w) of the paclitaxel is dissolved in 30 minutesor less in a solution of 50% methanol/50% water (v/v) in a USP II paddleapparatus operating at 75 RPM. pH 7 was used, and the solubility of thetaxanes are not effected by pH. In another embodiment, the dissolutionstudies are carried out at 37° C.

In a further aspect, the present invention provides composition,comprising including at least 95% by weight of docetaxel, wherein atleast 20% (w/w) of the docetaxel is dissolved in 30 minutes or less in asolution of 15% methanol/85% water (v/v) in a USP II paddle apparatusoperating at 75 RPM. pH 7 was used, and the solubility of the taxanesare not effected by pH. In another embodiment, the dissolution studiesare carried out at 37° C.

In a further embodiment, the composition comprises a suspension furthercomprising a pharmaceutically acceptable aqueous carrier. The suspensionof the invention comprises taxane particles and a liquid carrier. Theliquid carrier can be aqueous. The suspension excludes a solid excipientwithin which the paclitaxel is contained and excludes GELUCIRE®(polyethylene glycol glycerides composed of mono-, di- and triglyceridesand mono- and diesters of polyethylene glycol), and CREMOPHOR®(polyethoxylated castor oil).

Even though the paclitaxel particles do not include an added excipient,the liquid carrier of the suspension can comprise water and optionallyone or more excipients selected from the group consisting of buffer,tonicity adjusting agent, preservative, demulcent, viscosity modifier,osmotic agent, surfactant, antioxidant, alkalinizing agent, acidifyingagent, antifoaming agent, and colorant. For example, the suspension cancomprise taxane particles, water, buffer and salt. It optionally furthercomprises a surfactant. In some embodiments, the suspension consistsessentially of or consists of water, taxane particles suspended in thewater and buffer. The suspension can further contain an osmotic salt.

The suspension can comprise one or more surfactants. Suitablesurfactants include by way of example and without limitationpolysorbates, lauryl sulfates, acetylated monoglycerides, diacetylatedmonoglycerides, and poloxamers.

The suspension can comprise one or more tonicity adjusting agents.Suitable tonicity adjusting agents include by way of example and withoutlimitation, one or more inorganic salts, electrolytes, sodium chloride,potassium chloride, sodium phosphate, potassium phosphate, sodium,potassium sulfates, sodium and potassium bicarbonates and alkaline earthmetal salts, such as alkaline earth metal inorganic salts, e.g., calciumsalts, and magnesium salts, mannitol, dextrose, glycerin, propyleneglycol, and mixtures thereof.

In one embodiment especially suitable for intraperitoneal (IP)administration, the suspension may be formulated to be hyperosmolar(hypertonic), hyposmolar (hypotonic) or isosmolar (isotonic) withrespect to the fluid(s) of the IP cavity. In some embodiments, thesuspension may be isotonic with respect to fluid in the IP cavity. Insuch an embodiment, the he osmolality of the suspension can range fromabout 200 to about 380, about 240 to about 340, about 280 to about 300or about 290 mOsm/kg.

The suspension can comprise one or more buffering agents. Suitablebuffering agents include by way of example and without limitation,dibasic sodium phosphate, monobasic sodium phosphate, citric acid,sodium citrate hydrochloric acid, sodium hydroxide,tris(hydroxymethyl)aminomethane,bis(2-hydroxyethyl)iminotris-(hydroxymethyl)methane, and sodium hydrogencarbonate and others known to those of ordinary skill in the art.Buffers are commonly used to adjust the pH to a desirable range forintraperitoneal use. Usually a pH of around 5 to 9, 5 to 8, 6 to 7.4,6.5 to 7.5, or 6.9 to 7.4 is desired.

The suspension can comprise one or more demulcents. A demulcent is anagent that forms a soothing film over a mucous membrane, such as themembranes lining the peritoneum and organs therein. A demulcent mayrelieve minor pain and inflammation and is sometimes referred to as amucoprotective agent. Suitable demulcents include cellulose derivativesranging from about 0.2 to about 2.5% such as carboxymethylcellulosesodium, hydroxyethyl cellulose, hydroxypropyl methylcellulose, andmethylcellulose; gelatin at about 0.01%; polyols in about 0.05 to about1%, also including about 0.05 to about 1%, such as glycerin,polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, andpropylene glycol; polyvinyl alcohol from about 0.1 to about 4%; povidonefrom about 0.1 to about 2%; and dextran 70 from about 0.1% when usedwith another polymeric demulcent described herein.

The suspension can comprise one or more alkalinizing agents to adjustthe pH. As used herein, the term “alkalizing agent” is intended to meana compound used to provide an alkaline medium. Such compounds include,by way of example and without limitation, ammonia solution, ammoniumcarbonate, potassium hydroxide, sodium carbonate, sodium bicarbonate,and sodium hydroxide and others known to those of ordinary skill in theart

The suspension can comprise one or more acidifying agents to adjust thepH. As used herein, the term “acidifying agent” is intended to mean acompound used to provide an acidic medium. Such compounds include, byway of example and without limitation, acetic acid, amino acid, citricacid, nitric acid, fumaric acid and other alpha hydroxy acids,hydrochloric acid, ascorbic acid, and nitric acid and others known tothose of ordinary skill in the art.

The suspension can comprise one or more antifoaming agents. As usedherein, the term “antifoaming agent” is intended to mean a compound orcompounds that prevents or reduces the amount of foaming that forms onthe surface of the fill composition. Suitable antifoaming agents includeby way of example and without limitation, dimethicone, SIMETHICONE®,octoxynol and others known to those of ordinary skill in the art.

The suspension can comprise one or more viscosity modifiers thatincrease or decrease the viscosity of the suspension. Suitable viscositymodifiers include methylcellulose, hydroxypropyl methycellulose,mannitol and polyvinylpyrrolidone.

The suspension can comprise one or more osmotic agents such as thoseused for peritoneal dialysis. Suitable osmotic agents include icodextrin(a glucose polymer), sodium chloride, potassium chloride, and salts thatare also used as buffering agents.

As used herein, “pharmaceutically acceptable salts” of the taxanes are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of patients without undue toxicity, irritation,allergic response, and the like, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use, as well as thezwitterionic forms, where possible, of the taxanes. The term “salts”refers to the relatively non-toxic, inorganic and organic acid additionsalts of taxanes. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate,oleate, palmitate, stearate, laurate, borate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,naphthylate, mesylate, glucoheptonate, lactobionate, andlaurylsulphonate salts, and the like. These may include cations based onthe alkali and alkaline earth metals, such as sodium, lithium,potassium, calcium, magnesium, and the like, as well as non-toxicammonium, quaternary ammonium, and amine cations including, but notlimited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. (See, for example, Berge S. M. et al., “PharmaceuticalSalts,” J. Pharm. Sci., 1977; 66:1-19 which is incorporated herein byreference.)

In one embodiment, the composition comprises a dosage form of taxane insuspension (i.e.: with a pharmaceutically acceptable carrier and anyother components), in a dosage deemed suitable by an attending physicianfor an intended use. Any suitable dosage form may be used; in variousnon-limiting embodiments, the dosage form is adequate to provide about0.01 mg/kg to about 50 mg/kg of body weight per day. In various furtherembodiments, the dosage form is adequate to provide about 0.01 mg/kg toabout 45 mg/kg, about 0.01 mg/kg to about 40 mg/kg, about 0.01 mg/kg toabout 35 mg/kg, about 0.01 mg/kg to about 30 mg/kg, about 0.01 mg/kg toabout 25 mg/kg, about 0.01 mg/kg to about 20 mg/kg, about 0.01 mg/kg toabout 15 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.01 mg/kg toabout 5 mg/kg, or about 0.01 mg/kg to about 1 mg/kg of body weight perday. The suspension can be administered as is or can be diluted with adiluent, e.g. with saline water for injection optionally including abuffering agent and one or more other excipients, prior toadministration. For example, the volume ratio of suspension to diluentmight be in the range of 1:1-1:100 (v/v) or other suitable ratio.

In another aspect, the invention provides methods for treating a tumor,comprising administering to a subject with a tumor an amount effectiveto treat the tumor of the composition or suspension of any embodiment orcombination of embodiments of the invention. The inventors haveunexpectedly been able to produce compositions comprising the recitedtaxane particles that have a mean bulk density between about 0.050 g/cm³and about 0.15 g/cm³, and/or a specific surface area (SSA) of at least18 m²/g an SSA using novel methods for producing the particles asdescribed herein. Each of the increased specific surface area and thedecreased bulk density result in the significant increase in dissolutionrate for the taxane particles of the invention compared to theunprocessed or raw material, and the milled taxane product used forcomparison. This provides a significant improvement for use of thetaxane particles of the invention in, for example, tumor treatment.

As used herein, a “tumor” includes benign tumors, pre-malignant tumors,malignant tumors that have not metastasized, and malignant tumors thathave metastasized.

The methods of the invention can be used to treat tumor that issusceptible to taxane treatment, including but not limited to breasttumors, ovarian tumors, lung tumors, bladder tumors, prostate tumors,bone tumors, stomach tumors and pancreatic tumors. In one non-limitingembodiment, the tumor is located in whole or in part in theintraperitoneal cavity.

The subject may be any suitable subject with a tumor, including but notlimited to humans, primates, dogs, cats, horses, cattle, etc.

As used herein, “treat” or “treating” means accomplishing one or more ofthe following: (a) reducing the severity of the disorder; (b) limitingor preventing development of symptoms characteristic of the disorder(s)being treated; (c) inhibiting worsening of symptoms characteristic ofthe disorder(s) being treated; (d) limiting or preventing recurrence ofthe disorder(s) in patients that have previously had the disorder(s);and (e) limiting or preventing recurrence of symptoms in patients thatwere previously symptomatic for the disorder(s). Amounts effective forthese uses depend on factors including, but not limited to, the natureof the taxane (specific activity, etc.), the route of administration,the stage and severity of the disorder, the weight and general state ofhealth of the subject, and the judgment of the prescribing physician. Itwill be understood that the amount of the composition of suspension ofthe invention actually administered will be determined by a physician,in the light of the above relevant circumstances. In one non-limitingembodiment, an amount effective is an amount that provides between 0.01mg/kg to about 50 mg/kg of body weight per day.

The compositions may be administered via any suitable route, includingbut not limited to orally, pulmonary, intraperitoneally, subcutaneousinjection, intramuscular injection, or any other form of injection, asdeemed most appropriate by attending medical personnel in light of allfactors for a given subject. In one embodiment, the composition orsuspension is administered intraperitoneally, for example, when thetumor is located (at least in part) in the peritoneal cavity. In thisembodiment, the composition or suspension may be administered, forexample, by perfusion or as a bolus into the peritoneal cavity. In afurther embodiment, the administering may be initiated after removal ofascites fluid from the peritoneal cavity.

A dosing period is that period of time during which a dose of taxaneparticles in the composition or suspension is administered. The dosingperiod can be a single period of time during which the entire dose isadministered, or it can be divided into two or more periods of timeduring each of which a portion of the dose is administered.

A post-dosing period is that period of time beginning after completionof a prior dosing period and ending after initiating a subsequent dosingperiod. The duration of the post-dosing period may vary according to asubject's clinical response to the paclitaxel. The suspension is notadministered during the post-dosing period. A post-dosing period canlast at least 7 days, at least 14 days, at least 21 days, at least 28days, at least 35 days, at least 60 days or at least 90 days or longer.The post-dosing period can be kept constant for a subject or two or moredifferent post-dosing periods can be used for a subject.

A dosing cycle includes a dosing period and a post-dosing period.Accordingly, the duration of a dosing cycle will be the sum of thedosing period and the post-dosing period. The dosing cycle can be keptconstant for a subject or two or more different dosing cycles can beused for a subject.

In one embodiment, the administering is carried out more than once, andwherein each administration is separated in time by at least 21 days.

In another aspect, the invention provides methods for making compoundparticles, comprising:

(a) introducing (i) a solution comprising at least one solvent and atleast one solute comprising a compound of interest into a nozzle inlet,and (ii) a compressed fluid into an inlet of a vessel defining apressurizable chamber;

(b) passing the solution out of a nozzle orifice and into thepressurizable chamber to produce an output stream of atomized droplets,wherein the nozzle orifice is located between 2 mm and 20 mm from asonic energy source located within the output stream, wherein the sonicenergy source produces sonic energy with an amplitude between 10% and100% of the total power that can be generated using the sonic energysource during the passing, and wherein the nozzle orifice has a diameterof between 20 μm and 125 μm;

(c) contacting the atomized droplets with the compressed fluid, to causedepletion of the solvent from the atomized droplets, to produce compoundparticles;

wherein steps (a), (b), and (c) are carried out under supercriticaltemperature and pressure for the compressed fluid.

The methods of the invention involve contacting a solution, including asolvent with at least one compound of interest (including but notlimited to an active pharmaceutical ingredient, such as a taxane)dispersed in the solvent, with a compressed fluid at supercriticalconditions for the compressed fluid, so as to cause the compressed fluidto deplete the solvent and precipitate the compound away as extremelysmall particles.

The methods of the present invention provide a significant improvementover methods such as those disclosed in U.S. Pat. Nos. 5,833,891;5,874,029; 6,113,795; and 8,778,181 (incorporated herein by reference intheir entirety) using a compressed fluid in combination with appropriatesolvents to reproducibly precipitate compounds as fine particles thathave a narrow size distribution. The methods of the present inventionare capable of producing the particles of the invention withsignificantly improved bulk density, SSA, and dissolution properties,and thus significantly improved therapeutic benefits. The methodsprovide this significant improvement, at least in part, through use ofthe sonic energy source external to the nozzle and at the reciteddistance from the nozzle orifice to provide significantly enhanced sonicenergy and enhanced disruption of the solvent-solute flow as it exitsthe nozzle compared to the methods disclosed U.S. Pat. Nos. 5,833,891and 5,874,029 that use a converging-diverging nozzle to create the sonicenergy.

In one embodiment, the methods further comprise:

(d) contacting the atomized droplets produced in step (c) with ananti-solvent to cause further depletion of the solvent from the compoundparticles, wherein step (d) is carried out under supercriticaltemperature and pressure for the anti-solvent.

The methods of the invention utilize a sonic energy source locateddirectly in the output stream of the solute dissolved in the solvent.Any suitable source of sonic energy may be used that is compatible withthe methods of the invention, including but not limited to sonic horn, asonic probe, or a sonic plate. In various embodiments, the nozzleorifice is located between about 2 mm and about 20 mm, about 2 mm andabout 18 mm, about 2 mm and about 16 mm, about 2 mm and about 14 mm,about 2 mm and about 12 mm, about 2 mm and about 10 mm, about 2 mm andabout 8 mm, about 2 mm and about 6 mm, about 2 mm and about 4 mm, about4 mm and about 20 mm, about 4 mm and about 18 mm, about 4 mm and about16 mm, about 4 mm and about 14 mm, about 4 mm and about 12 mm, about 4mm and about 10 mm, about 4 mm and about 8 mm, about 4 mm and about 6mm, about 6 mm and about 20 mm, about 6 mm and about 18 mm, about 6 mmand about 16 mm, about 6 mm and about 14 mm, about 6 mm and about 12 mm,about 6 mm and about 10 mm, about 6 mm and about 8 mm, about 8 mm andabout 20 mm, about 8 mm and about 18 mm, about 8 mm and about 16 mm,about 8 mm and about 14 mm, about 8 mm and about 12 mm, about 8 mm andabout 10 mm, about 10 mm and about 20 mm, about 10 mm and about 18 mm,about 10 mm and about 16 mm, about 10 mm and about 14 mm, about 10 mmand about 12 mm, about 12 mm and about 20 mm, about 12 mm and about 18mm, about 12 mm and about 16 mm, about 12 mm and about 14 mm, about 14mm and about 20 mm, about 14 mm and about 18 mm, about 14 mm and about16 mm, about 16 mm and about 20 mm, about 16 mm and about 18 mm, andabout 18 mm and about 20 mm, from the sonic energy source.

In further embodiments, with reference to the Figures, as shown in FIG.3, the nozzle assembly 100 includes a vessel 102 defining apressurizable chamber 104. The vessel 102 includes a distal end 106 anda proximal end 108. The nozzle assembly 100 further includes an inlet110 of the pressurizable chamber 104 at the proximal end 108 of thevessel 102. The nozzle assembly 100 further includes a nozzle 112positioned within the pressurizable chamber 104. As shown in FIG. 3, thenozzle 112 includes an inlet tube 114 in fluid communication with theinlet 110 of the pressurizable chamber 104. In addition, the nozzle 112includes an outlet aperture 116. Further, as shown in FIG. 3, the nozzle112 is adjustable to alter a distance 118 between the proximal end 108of the vessel 102 and the outlet aperture 116 of the nozzle 112. Asshown in FIG. 3, the nozzle 112 is further adjustable to alter an angle120 between a longitudinal axis of the vessel 122 and a longitudinalaxis of the nozzle 124. In addition, the nozzle assembly 100 includes anoutlet 126 of the pressurizable chamber 104 at the distal end 106 of thevessel 102.

The nozzle assembly 100 may further include a first reservoir 128 and asecond reservoir 130. The first reservoir 128 may include a supply ofsolvent, while the second reservoir 130 may include a supply ofanti-solvent. The inlet 110 of the pressurizable chamber 104 may be influid communication with the first reservoir 128, and a second inlet 132of the pressurizable chamber 104 may be in fluid communication with thesecond reservoir 130. In one example, the first reservoir 128 is influid communication with the inlet tube 114 of the nozzle 112, such thatthe solvent enters the pressurizable chamber 104 through the nozzle 112.Other examples are possible as well.

The outlet aperture 116 of the nozzle 112 may include a plurality ofridges to create a vortex within the nozzle 112 such that the solventexits the nozzle 112 via turbulent flow. In another example, the nozzle112 may include a porous frit interior to the nozzle 112 such that thesolvent exits the nozzle 112 via turbulent flow. In yet another example,the outlet aperture 116 of the nozzle 112 may have a small diameter (asdiscussed in additional detail below) such that the solvent exits thenozzle 112 via turbulent flow. These various embodiments that causeturbulent flow may assist in mixing the solvent with the anti-solventwithin the pressurizable chamber 104. Further, the inlet tube 114 of thenozzle 112 may have an inner diameter with a range from about 1.5875 mmto about 6.35 mm. In one example, both the angle of the nozzle 112 andthe vertical position of the nozzle 112 may be adjusted manually by auser. For example, the nozzle 112 may be positioned on a verticalsupport that can be adjusted to alter the distance 118 between theproximal end 108 of the vessel 102 and the outlet aperture 116 of thenozzle 112. Further, the nozzle 112 may be rotated manually to adjustthe angle 120 between the longitudinal axis of the vessel 122 and thelongitudinal axis of the nozzle 124. In another example, the nozzleassembly 100 may include a motor coupled to the nozzle 112. In variousexamples, the motor may be configured to alter the distance 118 betweenthe proximal end 108 of the vessel 102 and the outlet aperture 116 ofthe nozzle 112 and/or alter the angle 120 between the longitudinal axisof the vessel 122 and the longitudinal axis of the nozzle 124. Such amotor may be an electric motor powered by electrical power, or may bepowered by a number of different energy sources, such as a gas-basedfuel or solar power. The motor may be coupled directly or indirectly tothe nozzle 112, such that when the motor is turned on the distance 118between the proximal end 108 of the vessel 102 and the outlet aperture116 of the nozzle 112 increases or decreases depending on the directionthe motor rotates. The motor may be coupled to a series of gears thatadjusts the distance 118 between the proximal end 108 of the vessel 102and the outlet aperture 116 of the nozzle 112 and/or adjusts the angle120 between the longitudinal axis of the vessel 122 and the longitudinalaxis of the nozzle 124, or the motor may be coupled to a pulley systemthat adjusts the distance 118 between the proximal end 108 of the vessel102 and the outlet aperture 116 of the nozzle 112 and/or adjusts theangle 120 between the longitudinal axis of the vessel 122 and thelongitudinal axis of the nozzle 124. Other configurations are possibleas well.

In another example, the nozzle 112 assembly may include an actuatorcoupled to the nozzle 112, where the actuator alters the distance 118between the proximal end 108 of the vessel 120 and the outlet aperture116 of the nozzle 112 and/or alters the angle 120 between thelongitudinal axis of the vessel 122 and the longitudinal axis of thenozzle 124. Such an actuator may be an electro-mechanical actuator,including an electric motor that converts a rotary motion of theelectric motor to a linear displacement via a linkage system. Otherpotential actuators are possible as well, such as hydraulic actuators,pneumatic actuators, piezoelectric actuators, linear motors, ortelescoping linear actuators, as examples.

In one example, as shown in FIGS. 3 and 4, the nozzle assembly furtherincludes a sonic energy source 134 positioned adjacent to the outletaperture 116 of the nozzle 112. In one example, the sonic energy source134 may include a sonic probe extending within the pressurizable chamber104. In another example, the sonic energy source 134 may include a sonicsurface positioned in the pressurizable chamber 104. The sonic wavesfrom the sonic energy source 134 cause the liquids in the pressurizablechamber 104 to shatter, thereby enhancing mixing of the solvent andanti-solvent solutions to create particles within the pressurizablechamber 104. In one example, the sonic energy source 134 is positionedat an angle of 45 degrees with respect to the longitudinal axis of thenozzle 124. Other angles are possible as well. In one example, the sonicenergy source 134 may be adjustable to alter a distance between theoutlet aperture 116 of the nozzle 112 and the sonic energy source 134.Further, the sonic energy source 134 may be adjustable to alter an anglebetween the sonic energy source 134 and the longitudinal axis of thenozzle 124.

Any suitable source of sonic energy may be used that is compatible withthe methods of the invention, including but not limited to sonic horn, asonic probe, or a sonic plate. In various further embodiments, the sonicenergy source produces sonic energy with an amplitude between about 1%and about 100% of the total power that can be generated using the sonicenergy source. In light of the teachings herein, one of skill in the artcan determine an appropriate sonic energy source having a specific totalpower output to be used. In one embodiment, the sonic energy source hasa total power output of between about 500 and about 900 watts; invarious further embodiments, between about 600 and about 800 watts,about 650-750 watts, or about 700 watts.

In various further embodiments, the sonic energy source produces sonicenergy with a power output between about 5% and about 100%, about 10%and about 100%, 20% and about 100%, about 30% and about 100%, about 40%and about 100%, about 50% and about 100%, about 60% and about 100%,about 70% and about 100%, about 80% and about 100%, about 90% and about100%, about 1% and about 90%, about 5% and about 90%, about 10% andabout 90%, about 20% and about 90%, about 30% and about 90%, about 40%and about 90%, about 50% and about 90%, about 60% and about 90%, about70% and about 90%, about 80% and about 90%, about 1% and about 80%,about 5% and about 80%, about 10% and about 80%, about 20% and about80%, about 30% and about 80%, about 40% and about 80%, about 50% andabout 80%, about 60% and about 80%, about 70% and about 80%, about 1%and about 70%, about 5% and about 70%, about 10% and about 70%, about20% and about 70%, about 30% and about 70%, about 40% and about 70%,about 50% and about 70%, about 60% and about 70%, about 1% and about60%, about 5% and about 60%, about 10% and about 60%, about 20% andabout 60%, about 30% and about 60%, about 40% and about 60%, about 50%and about 60%, about 1% and about 50%, about 5% and about 50%, about 10%and about 50%, about 20% and about 50%, about 30% and about 50%, about40% and about 50%, about 1% and about 40%, about 5% and about 40%, about10% and about 40%, about 20% and about 40%, about 30% and about 40%,about 1% and about 30%, about 5% and about 30%, about 10% and about 30%,about 20% and about 30%, about 1% and about 20%, about 5% and about 20%,about 10% and about 20%, about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, or about 100% of the total power that can be generatedusing the sonic energy source. In various embodiments, the sonic energysource produces sonic energy with power output of about 1%-80%, 20-80%,30-70%, 40-60%, or about 60% of the total power that can be generatedusing the sonic energy source. In light of the teachings herein, one ofskill in the art can determine an appropriate frequency to be utilizedon the sonic energy source. In one embodiment, a frequency of betweenabout 18 and about 22 kHz on the sonic energy source is utilized. Invarious other embodiments, a frequency of between about 19 and about 21kHz, about 19.5 and about 20.5, or a frequency of about 20 kHz on thesonic energy source is utilized.

In various further embodiments, the nozzle orifice has a diameter ofbetween about 20 μm and about 125 μm, about 20 μm and about 115 μm,about 20 μm and about 100 μm, about 20 μm and about 90 μm, about 20 μmand about 80 μm, about 20 μm and about 70 μm, about 20 μm and about 60μm, about 20 μm and about 50 μm, about 20 μm and about 40 μm, about 20μm and about 30 μm, between about 30 μm and about 125 μm, about 30 μmand about 115 μm, about 30 μm and about 100 μm, about 30 μm and about 90μm, about 30 μm and about 80 μm, about 30 μm and about 70 μm, about 30μm and about 60 μm, about 30 μm and about 50 μm, about 30 μm and about40 μm, between about 40 μm and about 125 μm, about 40 μm and about 115μm, about 40 μm and about 100 μm, about 40 μm and about 90 μm, about 40μm and about 80 μm, about 40 μm and about 70 μm, about 40 μm and about60 μm, about 40 μm and about 50 μm, between about 50 μm and about 125μm, about 50 μm and about 115 μm, about 50 μm and about 100 μm, about 50μm and about 90 μm, about 50 μm and about 80 μm, about 50 μm and about70 μm, about 50 μm and about 60 μm, between about 60 μm and about 125μm, about 60 μm and about 115 μm, about 60 μm and about 100 μm, about 60μm and about 90 μm, about 60 μm and about 80 μm, about 60 μm and about70 μm, between about 70 μm and about 125 μm, about 70 μm and about 115μm, about 70 μm and about 100 μm, about 70 μm and about 90 μm, about 70μm and about 80 μm, between about 80 μm and about 125 μm, about 80 μmand about 115 μm, about 80 μm and about 100 μm, about 80 μm and about 90μm, between about 90 μm and about 125 μm, about 90 μm and about 115 μm,about 90 μm and about 100 μm, between about 100 μm and about 125 μm,about 100 μm and about 115 μm, between about 115 μm and about 125 μm,about 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm,115 μm, or about 120 μm. The nozzle is inert to both the solvent and thecompressed fluid used in the methods.

In further examples, the system may include a plurality of nozzles, witheach nozzle positioned at a different angle between a longitudinal axisof the vessel and a longitudinal axis of the nozzle and/or a differentdistance between the nozzle orifice and the sonic energy source. A givennozzle of the plurality of nozzles may be chosen for a given productionrun to produce a certain type of particle having a given SSA.

Any suitable solvent and solute may be used; exemplary such solutes andsolvents are disclosed in U.S. Pat. Nos. 5,833,891 and 5,874,029. In onenon-limiting embodiment, the solute/compound comprises a taxane,including those discussed herein. In various other non-limitingembodiments, the solvent may comprise acetone, ethanol, methanol,dichloromethane, ethyl acetate, chloroform, acetonitrile, and suitablecombinations thereof. In one embodiment, the solute/compound ispaclitaxel and the solvent is acetone. In another embodiment, thesolute/compound is docetaxel and the solvent is ethanol. The solventsshould comprise at least about 80%, 85%, or 90% by weight of the overallsolution.

The compressed fluid is capable of forming a supercritical fluid underthe conditions used, and the solute that forms the particles is poorlysoluble or insoluble in the compressed fluid. As is known to those ofskill in the art, a supercritical fluid is any substance at atemperature and pressure above its critical point, where distinct liquidand gas phases do not exist. Steps (a), (b), and (c) of the methods ofthe invention are carried out under supercritical temperature andpressure for the compressed fluid, such that the compressed fluid ispresent as a supercritical fluid during these processing steps.

The compressed fluid can serve as a solvent for and can be used toremove unwanted components in the particles. Any suitable compressedfluid may be used in the methods of the invention; exemplary suchcompressed fluids are disclosed in U.S. Pat. Nos. 5,833,891 and5,874,029. In one non-limiting embodiment, suitable supercriticalfluid-forming compressed fluids and/or anti-solvents can comprise carbondioxide, ethane, propane, butane, isobutane, nitrous oxide, xenon,sulfur hexafluoride and trifluoromethane. The anti-solvent recited instep (d) to cause further solvent depletion, is a compressed fluid asdefined above, and may be the same compressed fluid used in steps (a-c),or may be different. In one embodiment, the anti-solvent used in step(d) is the same as the compressed fluid used in steps (a-c). In apreferred embodiment, the compressed fluid and the anti-solvent are bothsuper-critical carbon dioxide.

In all cases, the compressed fluid and anti-solvent should besubstantially miscible with the solvent while the compound to beprecipitated should be substantially insoluble in the compressed fluid,i.e., the compound, at the selected solvent/compressed fluid contactingconditions, should be no more than about 5% by weight soluble in thecompressed fluid or anti-solvent, and preferably is essentiallycompletely insoluble.

The supercritical conditions used in the methods of the invention aretypically in the range of from 1× to about 1.4×, or 1× to about 1.2× ofthe critical temperature of the supercritical fluid, and from 1× toabout 7×, or 1× to about 2×, of the of the supercritical pressure forthe compressed fluid.

It is well within the level of those of skill in the art to determinethe critical temperature and pressure for a given compressed fluid oranti-solvent. In one embodiment, the compressed fluid and anti-solventare both super critical carbon dioxide, and the critical temperature isat least 31.1° C. and up to about 60° C., and the critical pressure isat least 1071 psi and up to about 1800 psi. In another embodiment, thecompressed fluid and anti-solvent are both super critical carbondioxide, and the critical temperature is at least 35° C. and up to about55° C., and the critical pressure is at least 1070 psi and up to about1500 psi. It will be understood by those of skill in the art that thespecific critical temperature and pressure may be different at differentsteps during the processing.

Any suitable pressurizable chamber may be used, including but notlimited to those disclosed in U.S. Pat. Nos. 5,833,891 and 5,874,029.Similarly, the steps of contacting the atomized droplets with thecompressed fluid to cause depletion of the solvent from the droplets;and contacting the droplets with an anti-solvent to cause furtherdepletion of the solvent from the droplets, to produce particles of thecompound can be carried out under any suitable conditions, including butnot limited to those disclosed in U.S. Pat. Nos. 5,833,891 and5,874,029.

The flow rate can be adjusted as high as possible to optimize output butbelow the pressure limitations for the equipment, including the nozzleorifice. In one embodiment, the flow rate of the solution through thenozzle has a range from about 0.5 mL/min to about 30 mL/min. In variousfurther embodiments, the flow rate is between about 0.5 mL/min to about25 mL/min, 0.5 mL/min to about 20 mL/min, 0.5 mL/min to about 15 mL/min,0.5 mL/min to about 10 mL/min, 0.5 mL/min to about 4 mL/min, about 1mL/min to about 30 mL/min, about 1 mL/min to about 25 mL/min, about 1mL/min to about 20 mL/min, 1 mL/min to about 15 mL/min, about 1 mL/minto about 10 mL/min, about 2 mL/min to about 30 mL/min, about 2 mL/min toabout 25 mL/min, about 2 mL/min to about 20 mL/min, about 2 mL/min toabout 15 mL/min, or about 2 mL/min to about 10 mL/min. The solution ofdrug subject to the flow rate can be any suitable concentration, such asbetween about 1 mg/ml and about 80 mg/ml.

In one embodiment, the methods further comprise receiving the pluralityof particles through the outlet of the pressurizable chamber; andcollecting the plurality of particles in a collection device.

In such an embodiment, with reference to the Figures, as shown in FIG.5, the invention comprises a collection device 200 including a vessel202 defining a chamber 204. The vessel 202 includes a distal end 206 anda proximal end 208. The outer diameter of the vessel 202 may range fromabout 152.4 mm to about 914.4 mm. The collection device 200 furtherincludes an inlet port 210 extending from the proximal end 208 of thevessel 202. The inlet port 210 is in fluid communication with thechamber 204. The inlet port 210 may have an outer diameter ranging fromabout 12.7 mm to about 101.6 mm. Further, the collection device 200includes an outlet port 212 extending from the proximal end 208 of thevessel 202. As shown in FIGS. 7 and 8, the outlet port 212 is in fluidcommunication with the chamber 204, and the outlet port 212 includes aporous material 214 positioned between the chamber 204 and the outletport 212. The outer diameter of the outlet port may range from about12.7 mm to about 50.8 mm.

As shown in FIGS. 5-9, the collection device 200 may further include asampling tube 216 having a distal end 218 and a proximal end 220. Theouter diameter of the sampling tube 216 may range from about 6.35 mm toabout 25.4 mm. As shown in FIGS. 7 and 8, the proximal end 220 of thesampling tube 216 extends from the proximal end 208 of the vessel 202,and the distal end 218 of the sampling tube 216 extends into the chamber204. The sampling tube 216 may be configured to remove a small sample ofparticles from the chamber 204 during a particle production run in whichadditional particles are being formed. In particular, the sampling tube216 may include a sample thief that enables an operator to remove asmall sample of particles without opening the chamber 204 or removingthe sampling tube 216 from the rest of the collection device 200 duringprocessing. This enables an operator to test a small sample of particlesto ensure that the product is within specifications as the processcontinues to run. For example, particle size or residual solventanalysis may be performed on the sample. If the measured specificationsdo not match the desired specifications, the operating parameters of theparticle formation process may be suitably adjusted to correct thesituation before an entire batch of product with undesirablecharacteristics is created.

The porous material 214 positioned between the chamber 204 and theoutlet port 212 may take a variety of forms. In one example, the porousmaterial 214 is selected from the group consisting of a frit, a mesh, acloth. As one specific example, the porous material 214 may comprise ahigh-efficiency particulate arrestance (HEPA) filter. An example HEPAfilter may include a mat of randomly arranged fibers, the fiberscomposed of fiberglass and possessing diameters between about 0.5micrometers and about 2.0 micrometers. In another example, the porousmaterial 214 comprises a sintered filter having a distal end 222 and aproximal end 224. In such an example, the proximal end 224 of thesintered filter extends from the proximal end 208 of the vessel 202 andis coupled to the outlet port 212, and the distal end 222 of thesintered filter extends into the chamber 204. Such a sintered filter mayinclude a porous stainless steel filter cartridge, as an example. Otherporous materials are possible as well.

The inlet port 210 may include a coupling mechanism connects an outletof a particle filtration system to the inlet port 210. In one example,the coupling mechanism comprises one or more sanitary fittings. Inanother example, the coupling mechanism comprises a threaded connectionbetween the outlet of the particle filtration system to the inlet port210. In yet another example, the coupling mechanism comprises one ormore compression fittings. Other example coupling mechanisms arepossible as well.

Further, as shown in FIG. 9, the collection device 200 may furtherinclude a collection insert 226 positioned within the chamber 204 of thevessel 202, and a support frame 228 positioned between an interior wall230 of the chamber 204 and the collection insert 226. The collectioninsert 226 may be a plastic bag, as an example. As shown in FIG. 10, thesupport frame 228 may include a distal ring 232, a proximal ring 234,one or more support legs 236 connecting the distal ring 232 to theproximal ring 234, and a gasket 238 positioned adjacent to the proximalring 234. In one example, the gasket 238 may comprise a neoprene gasket.The vessel 202 may include a removable lid 240 that can be removed toaccess the collection insert 226 once particle collection is completed.In such an example, the collection insert 226 may be positioned withinthe chamber 204 of the vessel 202 such that top edge of the collectioninsert 226 folds over the top of the support frame 228 and is sealedbetween the gasket 238 and the removable lid 240 when the lid is in theclosed position. Other arrangements are possible as well.

In one particular example method, a solution of 65 mg/ml of paclitaxelis prepared in acetone. The nozzle and a sonic probe are positioned inthe pressurizable chamber approximately 8 mm apart. A stainless steelmesh filter with approximately 100 nm holes is attached to thepressurizable chamber to collect the precipitated paclitaxelnanoparticles. The supercritical carbon dioxide is placed in thepressurizable chamber of the manufacturing equipment and brought toapproximately 1200 psi at about 37° C. and a flow rate of 18 kg perhour. The sonic probe is adjusted to an amplitude of 60% of maximumoutput at a frequency of 20 kHz. The acetone solution containing thepaclitaxel is pumped through the nozzle at a flow rate of 2 mL/minutefor approximately 60 minutes. The precipitated paclitaxel agglomeratesand particles are then collected from the supercritical carbon dioxideas the mixture is pumped through the stainless steel mesh filter. Thefilter containing the nanoparticles of paclitaxel is opened and theresulting product is collected from the filter.

In one particular example method, a solution of 79.32 mg/ml of docetaxelis prepared in ethanol. The nozzle and a sonic probe are positioned inthe pressurizable chamber approximately 9 mm apart. A stainless steelmesh filter with approximately 100 nm holes is attached to thepressurizable chamber to collect the precipitated docetaxelnanoparticles. The supercritical carbon dioxide is placed in thepressurizable chamber of the manufacturing equipment and brought toapproximately 1200 psi at about 38° C. and a flow rate of 63 slpm(standard liters per minute). The sonic probe is adjusted to 60% oftotal output power at a frequency of 20 kHz. The ethanol solutioncontaining the docetaxel is pumped through the nozzle at a flow rate of2 mL/minute for approximately 95 minutes, until the drug solution isconsumed. The precipitated docetaxel agglomerates and particles are thencollected from the supercritical carbon dioxide as the mixture is pumpedthrough the stainless steel mesh filter. The filter containing thenanoparticles of docetaxel is opened and the resulting product iscollected from the filter.

Further, the system described above may be a component of a largerparticle production system. Such a particle production system mayinclude one or more nozzle assemblies such as those described above, asonic energy source positioned adjacent to the orifice of each nozzle,one or more particle filtration systems in communication with one ormore nozzle assemblies, and one or more particle collection devices incommunication with the one or more particle filtration systems. In oneexample, the one or more particle filtration systems comprise a tandemparticle filtration system including at least one high pressureharvesting filter system and at least one low pressure collection filtersystem in tandem and downstream to the harvesting filter. In such anexample, the particle production system may include at least twoparticle harvesting filters, two particle collection filters and twocollection devices.

In another aspect, the invention provides compound particles prepared bythe method of any embodiment or combination of embodiments of theinvention.

Examples Materials and Methods

Raw paclitaxel and docetaxel were purchased from Phyton Biotech (BritishColumbia, Canada), lot number FP2-15004 and DT7-14025, respectively.Both were characterized in their raw form. The milling of both drugs wasaccomplished using a Deco-PBM-V-0.41 mill (Deco). The milling conditionsfor both compounds were as follows:

Ball size=5 mm

RPM=600

Processing time=60 min

Room temperature.

Preparation of Paclitaxel Particles

A solution of 65 mg/ml of paclitaxel was prepared in acetone. A BETEMicroWhirl® fog nozzle (BETE Fog Nozzle, Inc) and a sonic probe(Qsonica, model number Q700) were positioned in the crystallizationchamber approximately 8 mm apart. A stainless steel mesh filter withapproximately 100 nm holes was attached to the crystallization chamberto collect the precipitated paclitaxel nanoparticles. The supercriticalcarbon dioxide was placed in the crystallization chamber of themanufacturing equipment and brought to approximately 1200 psi at about38° C. and a flow rate of 24 kg/hour. The sonic probe was adjusted to60% of total output power at a frequency of 20 kHz. The acetone solutioncontaining the paclitaxel was pumped through the nozzle at a flow rateof 4.5 mL/minute for approximately 36 hours. Paclitaxel nanoparticlesproduced had an average number-weighted mean size of 0.81 μm with anaverage standard deviation of 0.74 μm over three separate runs.

Preparation of Docetaxel Particles

A solution of 79.32 mg/ml of docetaxel was prepared in ethanol. Thenozzle and a sonic probe were positioned in the pressurizable chamberapproximately 9 mm (apart. A stainless steel mesh filter withapproximately 100 nm holes was attached to the pressurizable chamber tocollect the precipitated docetaxel nanoparticles. The supercriticalcarbon dioxide was placed in the pressurizable chamber of themanufacturing equipment and brought to approximately 1200 psi at about38° C. and a flow rate of 68 slpm. The sonic probe was adjusted to 60%of total output power at a frequency of 20 kHz. The ethanol solutioncontaining the docetaxel was pumped through the nozzle at a flow rate of2 mL/minute for approximately 95 minutes). The precipitated docetaxelagglomerates and particles were then collected from the supercriticalcarbon dioxide as the mixture is pumped through the stainless steel meshfilter. The filter containing the nanoparticles of docetaxel was openedand the resulting product was collected from the filter.

Docetaxel nanoparticles produced had an average number-weighted meansize of 0.82 μm with an average standard deviation of 0.66 μm over threeseparate ethanol runs.

Particle Size Analysis

Particle size was analyzed by both light obscuration and laserdiffraction methods. An Particle Sizing Systems AccuSizer 780 SIS systemwas used for the light obscuration method and Shimadzu SALD-7101 wasused for the laser diffraction method. Paclitaxel nanoparticles wereanalyzed using 0.10% (w/v) sodium dodecyl sulfate (SDS) in water as thedispersant. Docetaxel nanoparticles were analyzed using isopar G as thedispersant.

Paclitaxel suspensions were prepared by adding approximately 7 mL offiltered dispersant to a glass vial containing approximately 4 mg ofpaclitaxel particles. The vials were vortexed for approximately 10seconds and then sonicated in a sonic bath approximately 1 minute. Ifthe sample was already suspended, 1:1 solution of paclitaxel suspensionto 0.1% SDS solution was made, vortexed for 10 seconds, and sonicated inthe sonic bath for 1 minute.

Docetaxel suspensions were prepared by adding approximately 7 mL offiltered dispersant to a plastic vial containing approximately 4 mg ofdocetaxel particles. The vial was vortexed for approximately 10 secondsand then sonicated in a sonic bath for approximately 2 minutes. Thissuspension was used for laser diffraction analysis. Unused suspensionwas poured into a 125 mL particle-free plastic bottle, which was thenfilled to approximately 100 mL with filtered dispersant. The suspensionwas vortex for approximately 10 seconds and then sonicated in the sonicbath for approximately 2 minutes. This diluted suspension was used forlight obscuration analysis.

A background test was first performed prior to analyzing particles onthe AccuSizer 780 SIS. A new particle-free plastic bottle was filledwith blank suspension solution by pumping from a reservoir, using aperistaltic pump, through a 0.22 μm Millipore filter and into thebottle. A background analysis was run to ensure the particle/mL countwas below 100 particles/mL. A small amount of paclitaxel suspension,5-100 μL, depending upon concentration of solution, was pipetted intothe plastic bottle in place from the background test and was filled with˜100 mL dispersant and the analysis was started. Counts were monitoredand paclitaxel solution added to reach and/or maintain 6000-8000particle counts/mL during the entire analysis. Once the analysis wascompleted, the background data was removed and any measurement with lessthan four counts was removed.

To analyze particles on SALD-7101 using a batch cell, the analysis wasstarted by choosing Manual Measurement. The refractive index was set as1.5 to 1.7. The batch cell was filled with filtered dispersant just pastthe etched line. The blank measurement was ran. A small amount of API(paclitaxel or docetaxel) suspension was pipetted, generally <1 mL,depending upon concentration of solution as low as 100 into the batchcell as needed to achieve an acceptable absorbance between 0.15 and 0.2absorbance units. The measurements were executed, and the resultinggraph with the highest level of confidence was selected; background wasautomatically accounted for.

BET Analysis

A known mass between 200 and 300 mg of the analyte was added to a 30 mLsample tube. The loaded tube was then mounted to a Porous Materials Inc.SORPTOMETER®, model BET-202A. The automated test was then carried outusing the BETWIN® software package and the surface area of each samplewas subsequently calculated.

Bulk Density Analyte

Paclitaxel or docetaxel particle preparations were added to a 10 mLtared graduated cylinder through a plastic weigh funnel at roomtemperature. The mass of the drug was measured to a nearest 0.1 mg, thevolume was determined to the nearest 0.1 mL and the density calculated.

Dissolution Studies Paclitaxel

Approximately 50 mg of material (i.e.: raw paclitaxel, milledpaclitaxel, or paclitaxel particles) were coated on approximately 1.5grams of 1 mm glass beads by tumbling the material and beads in a vialfor approximately 1 hour. Beads were transferred to a stainless steelmesh container and placed in the dissolution bath containingmethanol/water 50/50 (v/v) media at 37° C., pH 7, and a USP Apparatus II(Paddle), operating at 75 rpm. At 10, 20, 30, 60, and 90 minutes, a 5 mLaliquot was removed, filtered through a 0.22 μm filter and analyzed on aU(V/V)is spectrophotometer at 227 nm. Absorbance values of the sampleswere compared to those of standard solutions prepared in dissolutionmedia to determine the amount of material dissolved.

Docetaxel

Approximately 50 mg of material (i.e.: raw docetaxel, milled docetaxel,or docetaxel particles) was placed directly in the dissolution bathcontaining methanol/water 15/85 (v/v) media at 37° C., pH 7, and a USPApparatus II (Paddle), operating at 75 rpm. At 5, 15, 30, 60, 120 and225 minutes, a 5 mL aliquot was removed, filtered through a 0.22 μmfilter, and analyzed on a UV/VIS spectrophotometer at 232 nm. Absorbancevalues of the samples were compared to those of standard solutionsprepared in dissolution media to determine the amount of materialdissolved.

Results

The BET surface area of particles produced using the above protocol andvariations thereof (i.e.: modifying nozzles, filters, sonic energysources, flow rates, etc.) ranged between 22 and 39 m²/g. FIG. 1 showsexemplary particles produced using the methods of the invention. Bycomparison, the BET surface area of raw paclitaxel was measured at 7.25m²/g (FIG. 2), while paclitaxel particles made according to the methodsof U.S. Pat. Nos. 5,833,891 and 5,874,029 ranged from 11.3 to 15.58m²/g. Exemplary particle sizes produced using the methods of theinvention are shown in Table 1.

TABLE 1 Surface Mean Size St Dev area μm μm m²/g Number Volume NumberVolume 1 38.52 0.848 1.600 0.667 0.587 2 33.82 0.754 0.988 0.536 0.486 335.90 0.777 1.259 0.483 0.554 4 31.70 0.736 0.953 0.470 0.466 5 32.590.675 0.843 0.290 0.381 6 38.22 0.666 0.649 0.344 0.325 7 30.02 0.6700.588 0.339 0.315 8 31.16 0.672 0.862 0.217 0.459 9 23.90 0.857 1.5600.494 0.541 10 22.27 0.857 1.560 0.494 0.541 11 26.19 0.861 1.561 0.4650.546

Comparative studies on bulk density, SSA, and dissolution rates (carriedout as noted above) for raw drug, milled drug particles, and drugparticles produced by the methods of the present invention are providedin Tables 2 and 3 below. The full dissolution time course for thepaclitaxel and docetaxel materials are provided in Tables 4 and 5,respectively.

TABLE 2 Compound: Paclitaxel Raw Particles Characteristic Material Batch1 Batch 2 Mean Milled Number 1.16 0.83 0.67 0.75 0.89 Mean (um) VolumeMean 1.29 1.42 0.57 1.00 1.35 (um) Bulk Density 0.26 0.060 0.11 0.0850.31 (g/cm³) Surface Area 10.4 35.6 39.8 37.7 15.0 (m²/g) Dissolution18% 42% 52% 47% 32% (30 min)

TABLE 3 Compound: Docetaxel Raw Particles Characteristic Material Batch1 Batch II Mean Milled Number 1.58 0.92 0.80 0.86 1.11 Mean (um) VolumeMean 5.05 4.88 4.03 4.46 3.73 (um) Bulk Density 0.24 0.062 0.096 0.0790.44 (g/cm³) Surface Area 15.9 43.0 45.4 44.2 15.2 (m²/g) Dissolution11% 27% 27% 27% 9% (30 min)

TABLE 4 Paclitaxel Dissolution time course Timepoint Paclitaxel(minutes) Raw Material Paclitaxel Particles Milled Paclitaxel 0 0.0%0.0% 0.0% 10 14.0% 40.2% 23.0% 20 17.8% 47.6% 30.0% 30 18.4% 51.9% 32.3%60 23.9% 58.3% 38.6% 90 28.6% 62.9% 43.5%

TABLE 5 Docetaxel Dissolution time course Timepoint Docetaxel (minutes)Raw Material Docetaxel Particles Milled Docetaxel 0 0.0% 0.0% 0.0% 53.2% 12.1% 3.2% 15 6.9% 21.7% 5.9% 30 11.2% 27.2% 9.3% 60 16.4% 32.9%12.2% 120 22.4% 38.9% 13.6% 225 26.8% 43.1% 16.0%

We claim:
 1. A method for treating a lung tumor, comprisingadministering to a subject with a lung tumor an amount effective totreat the tumor of a composition comprising particles including at least95% by weight of a taxane, or a pharmaceutically acceptable saltthereof, wherein the particles have a specific surface area (SSA) of atleast 18 m²/g, and wherein the taxane particles include bothagglomerated taxane particles and non-agglomerated taxane particles. 2.The method of claim 1, wherein the taxane is selected from the groupconsisting of paclitaxel, docetaxel, and cabazitaxel, or apharmaceutically acceptable salt thereof.
 3. The method of claim 2,wherein the taxane is paclitaxel or a pharmaceutically acceptable saltthereof.
 4. The method of claim 3, wherein the paclitaxel particles havea mean bulk density between about 0.050 g/cm³ and about 0.12 g/cm³. 5.The method of claim 3, wherein the paclitaxel particles have a specificsurface area (SSA) of at least 20 m²/g.
 6. The method of claim 3,wherein the paclitaxel particles have a SSA of between 18 m²/g and about40 m²/g.
 7. The method of claim 3, wherein the paclitaxel particles havea SSA of between about 20 m²/g and about 40 m²/g.
 8. The method of claim2, wherein the taxane is docetaxel or a pharmaceutically acceptable saltthereof.
 9. The method of claim 8, wherein the docetaxel particles havea mean bulk density between about 0.050 g/cm³ and about 0.12 g/cm³. 10.The method of claim 8, wherein the docetaxel particles have a SSA ofbetween 18 m²/g and about 50 m²/g.
 11. The method of claim 8, whereinthe docetaxel particles have a SSA of at least 20 m²/g.
 12. The methodof claim 8, wherein the docetaxel particles have a SSA of between about20 m²/g and about 50 m²/g.
 13. The method of claim 8, wherein thedocetaxel particles have a SSA of between about 25 m²/g and about 50m²/g.
 14. The method of claim 1, wherein the particles have a meanparticle size of between about 0.4 μm to about 3 μm.
 15. The method ofclaim 3, wherein the particles have a mean particle size of betweenabout 0.4 μm to about 3 μm.
 16. The method of claim 8, wherein thedocetaxel particles have a mean particle size of between about 0.4 μm toabout 3 μm.
 17. The method of claim 1, wherein the particles have a meanparticle size of between about 0.4 μm to about 1.2 μm.
 18. The method ofclaim 3, wherein the particles have a mean particle size of betweenabout 0.4 μm to about 1.2 μm.
 19. The method of claim 8, wherein thedocetaxel particles have a mean particle size of between about 0.4 μm toabout 1.2 μm.
 20. The method of claim 1, wherein the compositioncomprises a suspension further comprising a pharmaceutically acceptableaqueous carrier.
 21. The method of claim 3, wherein the compositioncomprises a suspension further comprising a pharmaceutically acceptableaqueous carrier.
 22. The method of claim 8, wherein the compositioncomprises a suspension further comprising a pharmaceutically acceptableaqueous carrier.
 23. The method of claim 1, wherein the taxane ispaclitaxel or a pharmaceutically acceptable salt thereof, the paclitaxelparticles have a SSA of between 18 m²/g and about 40 m²/g, thepaclitaxel particles have a mean bulk density between about 0.050 g/cm³and about 0.12 g/cm³, and the paclitaxel particles have a mean particlesize of between about 0.4 μm to about 3 μm.
 24. The method of claim 23,wherein the composition comprises a suspension further comprising apharmaceutically acceptable aqueous carrier.
 25. The method of claim 1,wherein the taxane is docetaxel or a pharmaceutically acceptable saltthereof, the docetaxel particles have a SSA of between 18 m²/g and about50 m²/g, the docetaxel particles have a mean bulk density between about0.050 g/cm³ and about 0.12 g/cm³, and the docetaxel particles have amean particle size of between about 0.4 μm to about 3 μm.
 26. The methodof claim 25, wherein the composition comprises a suspension furthercomprising a pharmaceutically acceptable aqueous carrier.